5-phenyl-benzotriazepin-2-one compounds and their production



United States Patent 3,176,008 S-PI-[ENYL-BENZGTRIAZEPIN-Z-0NE CUM- POUNDS AND THEIR PRGDUCTION Theodore S. Sulkowski, Narherth, and Scott J. Childress,

Newtown Square, Pa., assignors to American Home Products Corporation, New Yorlr, N.Y., a corporation of Delaware No Drawing. Filed Sept. 11, 1962, Ser. No. 222,940 7 Claims. (Cl. 260239.3)

This invention relates to a new class of psychotherapeutic heterocyclic compounds having valuable properties as anticonvulsants. These compounds are substituted 1,3-dihydro--aryl-2H-l,3,4benzotriazepin 2 ones and have the general formula:

NH \c I Ar I METHOD I h NH:

c=o X X i C NH COG] I N 1 'i' 2 \czN/ Ar l II I An alternative method for preparing the present compounds consists in heating a Z-amino-benzophenone (III) with a hydrazine acid ester as shown in the following equation:

where Y is an alkoxy group.

In preparative Method 1, a tertiary amine is employed together with a suitable inert solvent in order to react with the hydrogen chloride liberated in the reaction. Suitable tertiary amines include trirnethylamine, triethylamine, tributylamine and dimethylaniline. Suitable inert solvents include chloroform, methylene chloride, benzene and toluene.

For best results in carrying out Method I, it is recommended to slowly add a solution of phosgcne to a cooled solution containing the hydrazone and the tertiary amine. Preferably, the reaction temperature during this addition should not exceed about 10 C. After the addition of phosgene is completed, the mixture is stirred at room temperature, filtered and the filtrate is evaporated to dryice ness in vacuo. The residue is dissolved in hot ethanol and treated with charcoal and the product precipitates on standing.

In Method II, the benzophenone and the hydrazino acid ester reactant are heated under autogenous pressure at a temperature ranging from about to about 225 and preferably at C. The mixture is then cooled to room temperature, diluted with ethanol and filtered. The product precipitates upon standing.

The following Examples illustrate the practice of this invention:

Example 1 A solution of 12 g. of 12.5% phosgene in benzene solution is added dropwise to a cooled solution of 3.2 g. of Z-amino-benzophenone hydrazone and 5 ml. of triethylamine in 50 ml. of benzene. After addition is completed the mixture is stirred at room temperature for one hour, filtered, and the filtrate evaporated to dryness in vacuo. The residue is dissolved in hot ethanol and treated with charcoal. On standing 1,3-dihydro-5- phenyl-ZI-l-l,3,4-benzotriazepin-2-one, M.P. 238-2395 C., precipitates. Analysis calcd. for C I-1 N 02 C, 70.87; H, 4.68; N, 17.70. Found: C, 70.69; H, 4.53; N, 18.04.

Example 2 A solution of 8 g. of 12.5% phosgene in benzene solution is added dropwise to a cooled solution of 2 g. of 2-amino-S-methylbenzophenone hydrazone and 3 ml. of triethylamine in 50 ml. of benzene. The mixture is stirred an additional hour at room temperature, filtered, and the filtrate evaporated to dryness in vacuo. The residue is dissolved in hot ethanol and treated with charcoal. On standing 7-methyl-1,3-dihydro-5-phenyl-2H l,3,4-benzotriazepin-2-one, M.P. 253254.5 C., is obtained. Analysis calcd. for C H N O: C, 71.70; H, 5.21; N, 16.72. Found: C, 71.61; H, 5.43; N, 16.64.

Example 3 A mixture of 5 g. of 2-amino-S-chlorobenzophenone and 5 ml. of ethyl hydrazine carboxylate is heated at 190 for one hour. The mixture is cooled, diluted with 75 ml. of ethanol and filtered. On standing 7-chloro-1,3-dihydro-5-phenyl-2H-l,3,4-benzotriazepin-2-one, MI. 246- 248 C., precipitates. Analysis calcd. for C l-i N OClz C, 61.89; H, 3.72; N, 15.47. Found: C, 61.65; H, 3.95; N, 15.09.

Example 4 7-trifluoromethyl 1,3 dihydro 5 phenyl 2H 1, 3,4-benzotriazepin-2-one is prepared by heating 5 g. of 2-aminoS-trifluoromethyl benzophenone with 5 ml. of ethyl hydrazine carboxylate as described in Example 3.

Example 5 7-bromo 1,3 dihydro 5 phenyl-2H-1,3,4-benzotriazepin-Z-one is prepared by heating 5 g. of Z-arnino-S- bromo benzophenone with 5 ml. ethyl hydrazine carboxylate, as described in Example 3.

Example 6 As described in Example 3, 7-chloro-1,3-dihydro-5-ochlorophenyl-ZH-l,3,4-benzotriazepin-2-one is prepared by heating 5 g. of 2-amino-2'-5-dichloro benzophenone with ethyl hydrazine carboxylate.

Example 7 As described in Example 3, 7-nitro-1,3-dihydro-5- phenyl-2H-l,3,4-benzotriazepin-2-one is prepared by heating 5 g. of Z-amino-S-nitro benzophenone with 5 ml. of ethyl hydrazine carboxylate.

The compounds of this invention may be combined with suitable diluents, solvents, carriers and excipients, as required to provide dosage forms suitable for oral or parenteral administration.

From the teachings of the foregoing examples, it will be obvious to those skilled in the art how to prepare other similar compounds encompassed within the scope of the broader claims.

What is claimed is:

1. A compound having the formula it \C=O X I N-H o=o 5. 7 methyl 1,3 dihydro 5 phenyl 2H 1,3,4- 7

benzotriazepin-Z-one.

6. 7 chloro 1,3 dihydro S phenyl 2H 1,3,4- benzotriazepin-Z-one.

7. The method which comprises heating together a 2- aminobenzophenone having the formula wherein X is selected from the group consisting of hydrogen, nitro, halogen, lower alkyl and trifluoromethyl and Ar is selected from the group consisting of phenyl and monohalophenyl with a hydrazinoacyl compound having the formula:

wherein Y is a lower alkoxy group, to form a compound having the formula:

N \C=N/ I 7 Ar wherein X and Ar are as hereinabove.

References Cited by the Examiner Busch: Ber. Deut. Chern., vol. 27, pages 28972904 IRVING MARCUS, Primary Examiner.

NICHOLAS S. RIZZO, WALTER A. MODANCE,

Examiners,

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No, 3,176,008

March 30, 1965 Theodore S. Sulkowski et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, lines 12 to 18 the formula should appear as shown below instead of as in the patent:

X N H Ar Signed and sealed this 28th day of September 1965.

(SEAL) Allest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOUND HAVING THE FORMULA
 7. THE METHOD WHICH COMPRISES HEATING TOGETHER A 2AMINOBENZOPHENONE HAVING THE FORMULA 